30.6
Cancer Cell Migration through Invadopodia
Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are pres…
Invasive cancer cells develop special membrane protrusions called invadopodia for migration.
Invadopodia have two main structural components — F-actin and actin regulators.
The formation of an invadopodium begins with the activation of cortactin — a nucleation promoting factor.
Cortactin then recruits cofilin activated WASP and Arp 2/3 complexes near the membrane.
Next, cofilin dissociates from cortactin and starts severing actin filaments to generate free barbed ends for elongation.
The WASP and Arp2/3 proteins initiate new actin branches, pushing the membrane out, and elongating the invadopodium.
Soon after, fascin starts crosslinking the actin filaments to form parallel actin bundles within the invadopodium core.
As the invadopodium matures, the kinesins use the colocalized microtubule network to deliver vesicles with ECM-degrading proteases to the cell membrane.
The cancer cells release these proteases to break down the ECM and intravasate into a blood vessel.
Here, cortactin phosphorylation destabilizes the branched actin network and disassembles the invadopodia.
Similar to intravasation, the circulating cancer cells also use invadopodia to extravasate into the tissue and form secondary tumors.
View the full transcript and gain access to JoVE Core videos
Q1: What are the main structural components of invadopodia?
Invadopodia contain two primary structural components: F-actin and actin regulators. F-actin forms the core filamentous structure, while actin regulators like cortactin, cofilin, WASP, and Arp2/3 complexes control actin polymerization and branching. Fascin crosslinks actin filaments into parallel bundles that strengthen the invadopodium core, enabling it to penetrate the extracellular matrix.
Q2: How does cortactin initiate invadopodium formation?
Cortactin, a nucleation-promoting factor, activates at the cell membrane to begin invadopodium formation. It recruits cofilin-activated WASP and Arp2/3 complexes near the membrane. Cofilin then severs actin filaments to generate free barbed ends, while WASP and Arp2/3 initiate new actin branches that push the membrane outward, establishing the growing invadopodium structure.
Q3: What role do kinesins play in mature invadopodia?
Once invadopodia mature, kinesins use the colocalized microtubule network as tracks to transport vesicles containing extracellular matrix-degrading proteases from the Golgi to the cell membrane. These vesicles release enzymes such as matrix metalloproteases, cathepsins, and serine proteases at the invadopodium tip, enabling the cancer cell to break down surrounding tissue and facilitate intravasation into blood vessels.
Q4: How do invadopodia differ from podosomes?
Although both invadopodia and podosomes are classified as invadosomes with proteolytic activity, they differ significantly in structure and duration. Podosomes are short structures lasting only minutes, while invadopodia persist for hours and extend many microns in length. In tumors, invadopodia are essential for cell intravasation and extravasation through blood vessels, whereas podosomes function differently in macrophages and other normal cells.
Q5: What happens to invadopodia during cancer cell intravasation?
During intravasation, cortactin phosphorylation destabilizes the branched actin network and triggers invadopodium disassembly. This retraction allows cancer cells to enter blood vessels after proteases degrade the extracellular matrix. Similarly, circulating cancer cells use invadopodia to extravasate into tissues and establish secondary tumors, demonstrating the critical role of these structures throughout the metastatic process.
Q6: How does fascin contribute to invadopodium maturation?
Fascin crosslinks actin filaments within the invadopodium core to form parallel actin bundles. This bundling stabilizes and strengthens the structure during maturation, creating a rigid scaffold that supports protease delivery and extracellular matrix degradation. The organized actin architecture generated by fascin is essential for the invadopodium to function as an effective invasive structure.
Q7: Why are invadopodia important for tumor cell metastasis?
Invadopodia enable cancer cells to degrade and penetrate the extracellular matrix, facilitating intravasation into blood vessels and extravasation into distant tissues. Their ability to concentrate proteases at the cell membrane and persist for extended periods makes them essential for successful metastatic dissemination. Without functional invadopodia, cancer cells cannot efficiently breach tissue barriers to establish secondary tumors.